Two Major Loci Control Variation in β-Lipoprotein Cholesterol and Response to Dietary Fat and Cholesterol in Baboons

Abstract

Abstract-We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in ␤-lipoproteins (low density lipoprotein cholesterol [LDLC]) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels (LDLC Base ), we analyzed two variables for diet response: LDLC RF , which represents the LDLC response to increasing dietary fat (ie, high-fat diet minus baseline), and LDLC RC , which represents the LDLC response to increasing dietary cholesterol level (ie, high-cholesterol, high-fat diet minus high-fat diet). Heritabilities (h 2 ) of the 3 traits were 0.59 for LDLC Base , 0.14 for LDLC RF , and 0.59 for LDLC RC . In addition, LDLC Base and LDLC RC had a significant genetic correlation (ie, G ϭ0.54), suggesting that 1 or more genes exert pleiotropic effects on the 2 traits. Segregation analyses detected a single major locus that accounted for nearly all genetic variation in LDLC RC and some genetic variation in LDLC Base and LDLC RF and confirmed the presence of a different major locus that influences LDLC Base alone. Preliminary linkage analyses indicated that neither locus was linked to the LDL receptor gene, a likely candidate locus for LDLC. Detection of these major loci with large effects on the LDLC response to dietary cholesterol in a nonhuman primate offers hope of detecting and ultimately identifying similar loci that determine LDLC variation in human populations. (Arterioscler Thromb Vasc Biol. 1998;18:1061-1068.)

A pleiotropic QTL on 2p influences serum Lp-PLA2 activity and LDL cholesterol concentration in a baboon model for the genetics of atherosclerosis risk factors

“…Our estimates of residual heritability are consistent with previous findings from different researchers also describing the substantial effect of genes on Lp-PLA 2 [5,13] and LDL-C concentration [7,8].…”

“…In studies of humans and animals, genes have been shown to account for a moderate proportion of the variance − 36% to 59% -in LDL-C levels [7,8]. Published genome scans have mapped quantitative trait loci (QTLs) affecting LDL-C concentration in humans to multiple chromosomal regions that harbor candidate genes affecting the regulation of LDL metabolism, processing and transport [7,9,10].…”

“…To test this hypothesis, we conducted analyses to detect, characterize, and localize to specific chromosomal regions the effects of genes contributing pleiotropically to variation in both phenotypes in pedigreed baboons, a model species with documented utility for studies of the genetics of lipoproteins and other risk factors for cardiovascular disease [8,14,15].…”

Two Loci Affect Angiotensin I–Converting Enzyme Activity in Baboons

“…As previously described, 13 all baboons were subjected to the same dietary challenge, and serum samples were available on each animal on each of 3 diets: (1) basal diet, a baseline monkey diet (Wayne Teklad) that was low in fat (Ϸ4% of calories) and cholesterol (0.03 mg/kcal); (2) HCHF diet, a diet high in saturated fat (40% of calories from fat by the addition of lard) and cholesterol (1.7 mg/kcal); and (3) LCHF diet, a high fat-only diet (40% of calories from lard, 0.03 mg/kcal of cholesterol).…”

“…LDLC was assayed on all diet samples, and LDLC RC was calculated as the difference in LDLC between the HCHF and LCHF diets (LDLC HCHF ϪLDLC LCHF ). 13 Published human primers were used to amplify 279 homologous microsatellite loci from baboon genomic DNA samples. 14,15 Approximately two thirds of the genotypes and 236 of these highly polymorphic markers were generated by researchers at Axys Pharmaceuticals Inc and were used to develop the baboon genomic map.…”